Zinc induces protein phosphatase 2A （PP2A） inactivation and tau hyperphosphorylation through PP2A （tyrosine 307） phosphorylation in cells and the brain, but whether Zn2＋ has a direct inhibitory ...effect on PP2A is not clear. Here we explored the effect of Zn2＋ on PP2A and their direct interaction in vitro. The results showed that Zn2＋ mimicked the inhibitory effect of okadaic acid on protein phosphatase and prevented tau dephosphorylation in N2a cell lysates. PP2A activity assays indicated that a low concentration （10 pmol/L） of Zn2＋ inhibited PP2A directly. Further Zn2＋-IDA-agarose affinity binding assays showed that Zn2＋ bound to and inhibited PP2Ac（51l-270） but not PP2Ac（1.50） or PP2Ac（27.309）. Taken together, Zn2＋ inhibits PP2A directly through binding to PP2Ac（51-270） in vitro.
Sensitivity and pressure range are two significant parameters of pressure sensors. Existing pressure sensors have difficulty achieving both high sensitivity and a wide pressure range. Therefore, we ...propose a new pressure sensor with a ternary nanocomposite Fe
O
/C@SnO
. The sea urchin-like Fe
O
structure promotes signal transduction and protects Fe
O
needles from mechanical breaking, while the acetylene carbon black improves the conductivity of Fe
O
. Moreover, one part of the SnO
nanoparticles adheres to the surfaces of Fe
O
needles and forms Fe
O
/SnO
heterostructures, while its other part disperses into the carbon layer to form SnO
@C structure. Collectively, the synergistic effects of the three structures (Fe
O
/C, Fe
O
/SnO
and SnO
@C) improves on the limited pressure response range of a single structure. The experimental results demonstrate that the Fe
O
/C@SnO
pressure sensor exhibits high sensitivity (680 kPa
), fast response (10 ms), broad range (up to 150 kPa), and good reproducibility (over 3500 cycles under a pressure of 110 kPa), implying that the new pressure sensor has wide application prospects especially in wearable electronic devices and health monitoring.
The 2019 novel coronavirus has spread rapidly around the world. Cancer patients seem to be more susceptible to infection and disease deterioration, but the factors affecting the deterioration remain ...unclear. We aimed to develop an individualized model for prediction of coronavirus disease (COVID‐19) deterioration in cancer patients. The clinical data of 276 cancer patients diagnosed with COVID‐19 in 33 designated hospitals of Hubei, China from December 21, 2019 to March 18, 2020, were collected and randomly divided into a training and a validation cohort by a ratio of 2:1. Cox stepwise regression analysis was carried out to select prognostic factors. The prediction model was developed in the training cohort. The predictive accuracy of the model was quantified by C‐index and time‐dependent area under the receiver operating characteristic curve (t‐AUC). Internal validation was assessed by the validation cohort. Risk stratification based on the model was carried out. Decision curve analysis (DCA) were used to evaluate the clinical usefulness of the model. We found age, cancer type, computed tomography baseline image features (ground glass opacity and consolidation), laboratory findings (lymphocyte count, serum levels of C‐reactive protein, aspartate aminotransferase, direct bilirubin, urea, and d‐dimer) were significantly associated with symptomatic deterioration. The C‐index of the model was 0.755 in the training cohort and 0.779 in the validation cohort. The t‐AUC values were above 0.7 within 8 weeks both in the training and validation cohorts. Patients were divided into two risk groups based on the nomogram: low‐risk (total points ≤ 9.98) and high‐risk (total points > 9.98) group. The Kaplan‐Meier deterioration‐free survival of COVID‐19 curves presented significant discrimination between the two risk groups in both training and validation cohorts. The model indicated good clinical applicability by DCA curves. This study presents an individualized nomogram model to individually predict the possibility of symptomatic deterioration of COVID‐19 in patients with cancer.
This is the first study to present a nomogram model to individually predict the deterioration of COVID‐19 in cancer patients. Clinical symptoms, computed tomography image features, cancer types, and comorbidities were incorporated in the model. Risk stratification was carried out targeting cancer populations for COVID‐19 deterioration. Cancer type was a critical factor affecting symptomatic deterioration. The COVID‐19 patients with lymphoma had the highest risk score for symptomatic deterioration.
Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel ...the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.
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•HCC-cell-derived ectosomal PKM2 induces monocyte-to-macrophage differentiation•Remodeling tumor microenvironment by ectosomal PKM2 promotes HCC progression•Sumoylation facilitates PKM2 sorting into ectosomes in an ARRDC1-dependent manner•Macrophage-secreted CCL1 reinforces PKM2 ectosomal excretion in a feedforward loop
Hou et al. demonstrate that sumoylation facilitates ectosomal excretion of PKM2 from HCC cells, which remodels the tumor microenvironment to promote HCC progression through inducing monocyte-to-macrophage differentiation. Macrophage-secreted CCL1 in tumor microenvironment further enhances ectosomal excretion of PKM2. The plasma ectosomal PKM2 is a potential early diagnostic marker for HCC.
Abstract Supramolecular photosensitizers (supraPSs) have emerged as effective photodynamic therapy (PDT) agents. Here, we propose the assembling capacity of supraPSs as a new strategy to construct ...theranostic nanoplatform with versatile functions aming at high-performance tumor therapy. By coating tirapazamine (TPZ)-loaded mesoporous silica nanoparticles (MSNs) with layer-by-layer (LbL) assembled multilayer, the versatile nanoplatform (TPZ@MCMSN-Gd3+ ) was obtained with the formation of supraPSs via host-guest interaction and the chelation with paramagnetic Gd3+ . The TPZ@MCMSN-Gd3+ could be specifically uptaken by CD44 receptor overexpressed tumor cells and respond to hyaluronidase (HAase) to trigger the release of therapeutics. As confirmed by in vivo studies, TPZ@MCMSN-Gd3+ showed preferential accumulation in tumor site and significantly inhibited the tumor progression by the collaboration of PDT and bioreductive chemotherapy under NIR fluorescence/MR imaging guidance. Taken together, this supraPSs based strategy paves a new paradigm of the way for the construction of theranostic nanoplatform.
Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the ...perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.
The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report a proteomic analysis of 144 autopsy samples from ...seven organs in 19 COVID-19 patients. We quantified 11,394 proteins in these samples, in which 5,336 were perturbed in the COVID-19 patients compared to controls. Our data showed that cathepsin L1, rather than ACE2, was significantly upregulated in the lung from the COVID-19 patients. Systemic hyperinflammation and dysregulation of glucose and fatty acid metabolism were detected in multiple organs. We also observed dysregulation of key factors involved in hypoxia, angiogenesis, blood coagulation, and fibrosis in multiple organs from the COVID-19 patients. Evidence for testicular injuries includes reduced Leydig cells, suppressed cholesterol biosynthesis, and sperm mobility. In summary, this study depicts a multi-organ proteomic landscape of COVID-19 autopsies that furthers our understanding of the biological basis of COVID-19 pathology.
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•11,394 proteins are quantified in autopsy samples from 7 organs in 19 COVID-19 patients•Elevated expression of cathepsin L1 is detected in the COVID-19 lung tissue•Dysregulation of angiogenesis, coagulation, and fibrosis is detected in multiple organs•Systemic metabolic dysregulation is detected in multiple organs
A proteomics analysis of 144 autopsy samples from seven organs in 19 COVID-19 patients shows elevated expression of cathepsin L1, rather than ACE2, in the lung tissue and highlights dysregulation of angiogenesis, coagulation, and fibrosis in multiple organs, in addition to systemic hyperinflammation.
Finding the sparsest solutions to a tensor complementarity problem is generally NP-hard due to the nonconvexity and noncontinuity of the involved
ℓ
0
norm. In this paper, a special type of tensor ...complementarity problems with
Z
-tensors has been considered. Under some mild conditions, we show that to pursuit the sparsest solutions is equivalent to solving polynomial programming with a linear objective function. The involved conditions guarantee the desired exact relaxation and also allow to achieve a global optimal solution to the relaxed nonconvex polynomial programming problem. Particularly, in comparison to existing exact relaxation conditions, such as RIP-type ones, our proposed conditions are easy to verify.
To evaluate prevalence and associated factors for myopia in high school students in Beijing.
Grade 10 and 11 high school students were randomly selected from nine randomly selected districts of ...Beijing. The students underwent non-cylcoplegic auto-refractometry and an interview.
Out of 4798 eligible students, 4677 (93.4%) students (mean age:16.9±0.7years;range:16-18 years) participated. Mean refractive error of right eyes and left eyes was -2.78±2.29 diopters and -2.59±2.50 diopters, respectively. Prevalence of myopia (defined as ≤ -1.00 diopters in the worse eye) was 80.7% (95% Confidence Interval (CI): 79.6-81.8%). Out of 3773 students with myopia, 1525 (40.4%) wore glasses daily. In multiple logistic regression analysis, a higher prevalence of myopia was associated with female sex (odds ratio (OR) = 1.31;95%CI:1.11-1.55), Han ethnicity (OR = 1.64;95%CI:1.28-2.11), attending key schools (OR = 1.48;95%CI:1.24,1.77), higher family income (OR = 1.37;95%CI:1.09-1.71), longer time spent for near work (OR = 1.43;95%CI:1.06-1.93), shorter near work distance (OR = 1.87;95%CI:1.55-2.26), lower frequency of active rest during studying (OR = 1.40;95%CI:1.16-1.70), and parental myopia (OR = 2.28;95%CI:1.80-2.87). The interaction between distance from near work and time spent for near work was statistically (P = 0.03) significant. In multiple logistic regression analysis, higher prevalence of high myopia (≤-6.0 diopters) was associated with studying in key schools (OR = 1.38;95%CI:1.05,1.81), lower frequency of active rest during studying (OR = 1.40;95%CI:1.09,1.79), and a higher number of myopic parents (OR = 2.66;95%CI:2.08,3.40).
A prevalence of about 80% for myopia and a prevalence of about 10% for high myopia in students aged 16 to 18 years and attending classes of grade 10 and 11 in a Chinese metropolitan region is another example of the high prevalence of moderate and high myopia in metropolitan areas of China. With this young myopic generation getting older, myopia as cause for visual impairment and blindness may further increase in importance. Future studies may address whether active rests during studying with looking into the distance are preventive against myopia development or progression.
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